Download Genetic Testing for Epilepsy

Epilepsy
Genetic Testing for Epilepsy
A Guide for Clinicians
KNOWING WHAT TO LOOK FOR
KNOWING WHERE TO LOOK
AND KNOWING WHAT IT MEANS
Figure 1.
Introduction
Epilepsy is a common neurological disorder that affects at least 0.8% of the population. It is
defined by the occurrence of at least two unprovoked seizures occurring more than 24 hours
apart. Seizures are the manifestation of abnormal hypersynchronous discharges of cortical
neurons lasting for several seconds, minutes, or longer. The clinical presentation of seizures
depends upon both the location of the epileptic discharges in the cortex and the extent and
pattern of propagation of the electrical discharges in the brain.
In many cases, seizures result in convulsions and loss of consciousness. Seizures may also
manifest in other ways that affect personality, mood, memory, sensation, and/or movement. Blank
stares, lip smacking, intermittent eye movements, and jerking movements of the extremities are
all examples of possible manifestations of seizures. In some cases these may not be recognized
as a seizure by patients, their family members, or even health care professionals. Seizures can
be classified into various categories (Figure 1).
PLEASE REDRAW to make it look similarly to the one in the guide.
FIGURE 1: Types of seizures.
Generalized Tonic-Clonic 12-24%
Complex Partial 8-31%
Absence 5-22%
Simple Partial 2-12%
Infantile Spasms 1-9%
Myoclonic 1-11%
Other Partial 7-29%
Other Generalized <1-3%
Unclassified / Mixed 4-43%
Reference: Cowan, LD. The epidemiology of the epilepsies in children. Ment Retard Develop
Disab (2002) 8:171-181.
Etiology
Epilepsy may be an isolated neurological symptom, or it may occur as part of a more complex
syndrome. There are many different causes of epilepsy, including genetic disorders, metabolic
diseases, and structural brain abnormalities. However, in some cases, the cause of epilepsy
is not known. The International League against Epilepsy (ILAE) has described the underlying
causes of epilepsy as the following.3
Genetic: “The concept of genetic epilepsy is that the epilepsy is, as best as understood, the
direct result of a known or presumed genetic defect(s) in which seizures are the core symptom
GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS
1
of the disorder.”3 The genetic contribution must be evident by extensive and replicable molecular
studies or familial studies, e.g., SCN1A gene has been demonstrated to be associated with GEFS+.9
Structural/metabolic: If there is a specific structural or metabolic disorder that has been proven
in various studies to be associated with increased risk of epilepsy, the cause of epilepsy can
be defined as structural or metabolic. The cause for such a disorder can be acquired (e.g.,
trauma, stroke, infection), genetic (e.g., malformations of cortical development) or both (e.g.,
West syndrome).
Unknown cause: This means that the underlying cause is yet unknown. Epilepsy might be
presenting because of either some genetic defect or as a result of disorder that is not yet
recognized.
Diagnosis of Epilepsy
Clinical and family history
The detailed clinical history may help confirm that the seizure events are in fact epileptic seizures,
rather than non-epileptic events such as fainting, breath-holding, transient ischemic attacks,
strokes, arrhythmias, or hypoglycemia, all of which can manifest similarly to epileptic seizures.
A detailed clinical history also may help clarify potential triggers and diurnal patterns related to
seizure events. The medical history will help to determine if the seizures are isolated or part of a
larger syndrome. In addition to clinical history for the affected individual, a family medical history
should be obtained, including any history of seizures and other neurodevelopmental disorders
in any relatives. This information may help clarify the type of epilepsy in a family, including the
mode of inheritance and the prognosis.
Electroencephalogram (EEG)
Children with a known or suspected diagnosis of epilepsy based on clinical and family history
should undergo an EEG to help confirm the seizure type, and to evaluate recurrence risk for
future seizures. An EEG may also provide important information for making treatment decisions
(Figure 2).
Physical examination
In some cases, an individual with epilepsy may have other related neurological abnormalities,
medical problems, or dysmorphic features that can be identified by physical examination. For
example, many genetic syndromes involving epilepsy also cause developmental delay, hypotonia,
birth defects, ataxia, dystonia, microcephaly or macrocephaly, dysmorphic facial features, or
other features that can be noted in a physical examination.
Genetic testing
The information obtained from clinical and family histories, physical examination, and EEG can
help a clinician determine whether genetic testing should be offered to a patient with epilepsy
and which specific genetic test(s) may be appropriate.2
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Genetics of Epilepsy
The last decade has witnessed the discovery
of many genes involved in epilepsy. Most
of these genes are expressed in the brain
and encode subunits of ion channels that
play vital roles in stabilizing or propagating
neuronal activity. Disruption of these genes
in general induces neuronal hyperexcitability,
thus causing seizures. As described above,
there are many forms of epilepsies. A single
gene may be associated with different
forms of epilepsy, but one type of epilepsy
may also result from defects in any one
of a variety of genes.5 Inherited channels
caused by mutations in ion channel or
neuroreceptor genes (e.g., SCN1A-related
disorders and KCNQ2, KCNQ3 mutations
in benign familial neonatal seizures) can
present with seizures.9 Rarely epilepsy
syndromes can be the result of severe
mutations in single genes whereas more
commonly epilepsy is likely to be caused
by the combined effect of variants in a
number of genes that cannot be currently
defined. Examples of monogenic causes of
epilepsy are pyridoxine-dependent epilepsy
and neuronal ceroid lipofuscinoses (NCL).
In some cases, copy number variations
associated with neuropsychiatric disorders
can be involved in epilepsy too. It is well
known that the 1p36 microdeletion, WolfHirshhorn, Miller-Dieker, Pallister-Killian, and
Angelman syndromes include epilepsy as
a major feature, but these disorders also
involve various other clinical features as
well.2 Table 1 shows the common genetic
disorders that have been associated
with epilepsy. Some rare mitochondrial
disorders, such as MERRF and MELAS
can also present with epilepsy as one of
the symptoms.1
FIGURE 2: Typical EEG abnormalities for
different types of seizures.
Normal EEG (9yr-old child)
Modified hypsarrhythmia during sleep in patient
with infantile spasms (8mo-old infant)
Generalized spike wave in
patient with absence epilepsy (3yr-old child)
GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS
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Table 1: Genetic disorders associated with Epilepsy
Syndrome
Clinical Presentation
Inheritance
Genes
Adenylosuccinate
lyase deficiency
Psychomotor delay, intellectual disability,
intractable seizures ± autism
AR
ADSLI,C,A
Angelman/Angelmanlike syndromes
Developmental delay, onset
at >6 months of age, ataxia,
tremulousness, ‘‘happy’’ appearance, microcephaly, seizures
AD
CNTNAP2I,C,A
SLC9A6I,C,A
NRXN1I,C,A
TCF4I,C,A
UBE3AI,C,A
Autosomal dominant
nocturnal frontal
lobe epilepsy
Seizures arising from sleep,
prominent motor manifestations
AD
CHRNA2C,A
CHRNA4C,A
CHRNB2C,A
Autosomal dominant
partial epilepsy with
auditory features
Ictal auditory symptoms and
receptive aphasia, ± secondary
generalization, benign course
AD
LGI1C,A
Baltic myoclonus
(Unverricht-Lundbord
disease)
Individuals in late childhood or
adolescence with photosensitive
myoclonus, seizures, ataxia
AR
CSTBC,A,P
Benign familial
neonatal-infantile
seizures (BFNIS)
Seizures from 2 days of age to
6 months, normal development
AD
SCN2A,I,C
Benign familial neonatal
seizures (BFNS)
Neonatal seizures at approximately 3
days of age, resolution at <1 month of
age, generalized or focal tonic-clonic
seizures, normal development
AD
KCNQ2I, KCNQ3I
Creatine deficiency
syndromes
Developmental delay, seizures,
positive magnetic resonance
spectroscopy,± autism
Various
GAMTI,C, GATMC
SLC6A8C
Early-onset epileptic
encephalopathy and/
or infantile spasms
Early onset, multiform and
intractable seizures, cognitive,
behavioral, and neurological
Various
ALDH7A1I, ARXI
ATP6AP2I
CDKL5I,C
PCDH19I,C
POLGI,C,A
PNPOI, SCN1AI,C
SLC2A1I,C,A
SLC25A22I
SPTAN1I
STXBP1I
Epilepsy with variable
learning and behavioral
disorders
Variable clinical presentations with combinations of epilepsy, learning difficulties,
macrocephaly, and aggressive behavior
XL
SYN1C,A
Generalized epilepsy
with febrile seizures
plus (GEFS+)
Onset of febrile seizures at <1 year of
age, persistence beyond age 6 years,
evolution to mixed seizure types
AD
GABRG2I,C
SCN1AI,C
SCN1BI,C
SCN2AI,C
Superscript indicates the panels on which the genes are present. I = infantile epilepsy panel; C = Childhoodonset epilepsy panel; A= Adolescent onset epilepsy panel; P = Progressive myolconic epilepsy panel
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Syndrome
Clinical Presentation
Inheritance
Genes
Glucose transporter
Type I deficiency
syndrome
Early-onset refractory seizures,
movement disorders, ataxia, progressive encephalopathy, acquired
microcephaly, and spasticity
AD
SLC2A1I,C,A
Juvenile Myoclonic
Epilepsy (JME)
Typically seizures begin between
late childhood and early adulthood,
characterized by quick jerks of the arms,
shoulder, or occasionally the legs
AD
CACNB4C,A
EFHC1C,A
GABRA1C,A
Lafora disease
Progressive myoclonus, myoclonic
epilepsy, absences, and dementia
AR
EPM2AC,A,P
EPM2BC,A,P
Microcephaly with
early-onset intractable
seizures and developmental delay (MCSZ)
Infantile-onset seizures accompanied
by microcephaly developmental
delay and various behavioral
problems (typically hyperactivity)
AR
PNKPI
Mowat-Wilson
syndrome
Distinctive facial features, Hirschsprung
Disease, intellectual disabilities, genital
abnormalities, congenital heart disease,
agenesis of the corpus callosum, seizures,
eye defects and severe speech impairment.
Various
ZEB2I,C
Neuronal Ceroid
Lipofuscinoses (NCL)
Intellectual and motor deterioration,
seizures, visual loss, and early mortality
AR
CLN3I,C,A,P
CLN5I,C,A,P
CLN6I,C,A,P
CLN8I,C,A,P
CTSDI,C,A,P
MFSD8I,C,A,P
PPT1I,C,A,P
TPPI,C,A,P
Ohtahara syndrome
Suppression burst on electroencephalogram, tonic seizures
Various
STXBP1I, ARXI
Progressive Myoclonic
Epilepsy (PME)
Myoclonic seizures, cognitive
impairment, ataxia, and dementia
AR
PRICKLE1C,A,P
Pyridoxine dependent seizures
Vitamin B6-responsive seizures
AR
ALDH7A1I
Rett/Atypical Rett
syndrome
Rett Syndrome: Regression then
stagnation, onset at <18 months of
age, loss of purposeful hand movements, acquired microcephaly
Atypical Rett Syndrome:
Early-onset seizure variant of Rett
syndrome, ± Infantile spasms
Various
CDKL5I,C
FOXG1I,C
MECP2I,C
West Syndrome
Infantile spasms, hypsarrhythmia, encephalopathy
Various
TSC1I, TSC2I
CDKL5I,C, ARXI
STXBP1
There are 4 subpanels and a comprehensive panel available to order. ATP1A2 and SRPX2 are not part of any subpanel,
but are included in the comprehensive panel along with all the other genes listed in this table.
Superscript indicates the panels on which the genes are present. I = infantile epilepsy panel; C = Childhoodonset epilepsy panel; A= Adolescent onset epilepsy panel; P = Progressive myolconic epilepsy panel
GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS
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Clinical Utility of Genetic Testing
Genetic testing for epilepsies is often complex because mutations in so many different genes
can cause seizures. Nevertheless, genetic testing can be useful in certain clinical scenarios
when it can help in clarifying the prognosis, assist in treatment and management of the patient,
and predict the risk of a disease in family members. Genetic testing is termed ‘diagnostic’ if
the patient is symptomatic and ‘predictive’ if the patient is asymptomatic, but at risk for having
a disorder in the future.1
TABLE 2: Clinical utility of genetic testing
1. Diagnostic testing in an individual with epilepsy
• Confirm a clinical diagnosis of a specific genetic syndrome or type of epilepsy
• Distinguish between syndromic and non-syndromic forms of epilepsy
• Establish the genetic cause of idiopathic epilepsy
• Provide information about prognosis
2. Assistance with selection of optimal treatment options
3. Predictive testing for asymptomatic family members of a proband with a known disease-causing mutation associated with a genetic form of epilepsy
• Enable clinical monitoring, follow-up, and optimal treatment when symptoms
develop in an individual with a positive result
• Reduce anxiety and forego clinical monitoring if result is negative
4. Prenatal diagnosis in at-risk pregnancies for known, pathogenic mutations
5. Genetic counseling, recurrence risk determination, and family planning
Utility of genetic testing in treatment:
The treatment of epilepsy depends upon the type of seizure, age of the patient, and other factors.
Knowledge of the genetic etiology of epilepsy may guide selection of the most appropriate
treatment options in some cases. A number of antiepileptic medications are used in the treatment
of epilepsy. The specific type and etiology of seizures may influence the selection of antiepileptic
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medication for each patient. For example, certain medications may be more effective for infantile
spasms and are therefore first choices for patients with spasms. Likewise, certain medications
may be contraindicated for patients with a specific electroclinical or genetic diagnosis (Table
3). Dietary modifications including the ketogenic diet are useful in certain conditions1 such as
for patients with glucose transporter type 1 deficiency syndrome (SLC2A1 gene).
TABLE 3: Genetic test results applied to therapeutic decision-making
Disorder
Genes
Treatment Implications
Alpers-Huttenlocher and other
POLG-related disorders
POLG
Avoid valproic acid, which can
induce or accelerate liver disease
Creatine deficiency syndromes
SLC6A8,
GAMT, GATM
Oral creatine (GAMT, AGAT)
GEFS+, and other SCN1Arelated disorders
SCN1A
Valproate, clobazam, stiripentol, levetiracetam, topiramate. Avoid phenytoin,
carbamazepine, and lamotrigine.
Glucose transporter type
1 deficiency syndrome
SLC2A1
Seizures typically respond
to a ketogenic diet
Pyridoxal 5’-phosphatedependent epilepsy
PNPO
Seizures respond to treatment with
supplemental pyridoxal 5-phosphate (PLP)
Pyridoxine-dependent epilepsy
Folinic-acid responsive seizures
ALDH7A1
Seizures respond to treatment with supplemental vitamin B6 and/or folinic acid
Lafora disease
EPM2A, EPM2B
Avoid phenytoin, lamotrigine,
carbamazepine, and oxcarbazepine
Unverricht-Lundborg disease
CSTB
Avoid sodium channel blockers and
GABAergic drugs, which can increase
myoclonus, dementia, and ataxia
West syndrome
TSC1, TSC2,
CDKL5 (STK9),
ARX, STXBP1,
MEF2C
Vigabatrin for infantile spasms with TSC
GENE TIC TESTING FOR EPILEPSIES: A GUIDE FOR CLINICIANS
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Genetic Test Results and What They Mean
There are three possible outcomes of genetic testing: a positive result, a negative result, or a
variant of unknown significance (VUS).2
Positive:
A positive result indicates that a disease-causing mutation was identified in the tested individual.
This finding confirms the diagnosis of a particular type of epilepsy and provides valuable information
to the physician and family members about treatment, prognosis, and recurrence risk. All
first-degree relatives (e.g., children, siblings, and parents) of a patient with a positive genetic
test result can then be offered predictive genetic testing. If a family member is found to be
positive for the familial mutation, this individual is also at risk to develop the epilepsy syndrome
and should be referred for further evaluation. It is important to note that there is variability in
symptoms, age of onset, severity, and response to therapeutic agents, even among members
of the same family who have the same genetic mutation causing epilepsy.
Negative:
A negative result in an individual with epilepsy does not rule out a genetically inherited epilepsy
syndrome. Possible reasons for a negative result could be (1) the patient has a mutation in
a gene not included in the testing panel, (2) the patient may have a mutation in a part of an
epilepsy gene that was not covered by the test, or (3) the patient does not have a heritable form
of epilepsy. A negative result obtained in a specific genetic test in an individual with epilepsy
indicates that predictive of asymptomatic family members will not be informative for that same
test, and is not warranted. However, family members of a clinically affected individual with
negative test results may still be at risk for epilepsy syndromes and thus should be evaluated
by a neurologist if indicated.
If an asymptomatic individual is negative for a mutation identified in a family member with epilepsy,
the result is considered a “true negative.” This indicates that the individual is not at increased
genetic risk for the familial epilepsy syndrome and instead has the same risk as a person in
the general population to develop seizures. Specific clinical monitoring for the development of
seizures is not necessary in individuals with a “true negative” result.
Variant of Unknown Significance:
One of the most difficult results to interpret is the finding of a variant of unknown clinical significance
(VUS). This situation indicates that the pathogenic role of the variant cannot be clearly established.
In some cases, testing of other family members may help clarify the clinical significance of a
VUS. If other relatives with epilepsy are found to have the same variant, it is more likely that
the variant is disease-causing. The greater the number of affected family members who carry
the VUS, the greater is the likelihood that the VUS is pathogenic. Likewise, if an individual has
apparently sporadic epilepsy, the finding that a VUS is de novo (arose new in that individual and
was not inherited from a parent) indicates that the variant is likely disease-causing.
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References:
1. Pong, et al. Developments in molecular genetic diagnostics: An update for the pediatric epilepsy
specialist, Pediatr Neurol (2011) 44:317-327.
2. Pal, et al. Genetic evaluation and counseling for epilepsy. Nat Rev Neurol (2010) 6:445-453.
3. Berg, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the
ILAE Commission on Classification and Terminology, 2005-2009. Epilepsia (2010) 51: 676-685.
4. Deprez, et al. Genetics of epilepsy syndromes starting in the first year of life. Neurology (2009)
72:273-281.
5. Baulac, S and Baulac, M. Advances on the genetics of Mendelian idiopathic epilepsies. Neurol Clin
(2009) 27:1041-1061.
6. Macdonald, et al. Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol
(2010) 588:1861-1869.
7. Ottman, et al. Genetic testing in the epilepsies – Report of the ILAE Genetics Commission. Epilepsia
(2010) 51:655-670.
8. Ramachandran, et al. The autosomal recessively inherited progressive myoclonus epilepsies and their
genes. Epilepsia (2009) 50:29-36.
9. Steinlein, et al. Genetic mechanisms that underlie epilepsy. Nat Rev Neurosci (2004) 5:401-408.
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